Advances in the fields of genomics and proteomics have helped to advance basic knowledge of cancer biology leading to identification of cancer biomarkers and development of new methods of diagnosis and disease prognosis. Biomarkers are biological molecules that are indicators of physiologic state and also of change during a disease process.
The utility of a biomarker lies in its ability to provide an early indication of the disease, to monitor disease progression, to provide ease of detection, and to provide a factor measurable across populations. The sequencing of the human genome has set the pace for biomarker discovery and provided the impetus for the next level of molecular inquiry, which is represented by functional genomics or proteomics. These approaches have led to the identification of numerous molecular signatures for either prognosis or prediction of a diverse array of cancers linked to specific disease phenotypes. However, only a limited number of these have been validated, commercialized and brought forward to the clinic. To be clinically useful, a molecular signature should have independent predictive value superior to pathological staging. An alternative method of detecting biomarkers is referred to candidate approach, whereby a selected protein is tested as candidate biomarker by its expression levels and its physiological role in the cancer pathogenesis.
It has been reported that NPRA expression and signaling is important for tumor growth (3). NPRA-deficient mice showed significantly reduced antigen-induced pulmonary inflammation. NPRA deficiency also substantially protected C57BL/6 mice from lung, skin, and ovarian cancers. Furthermore, a nanoparticle-formulated interfering RNA for NPRA attenuated B16 melanoma tumors in mice. Ectopic expression of a plasmid encoding NP73-102, the NH(2)-terminal peptide of the ANP prohormone, which down-regulates NPRA expression, also suppressed lung metastasis of A549 cells in nude mice and tumorigenesis of Line 1 cells in immunocompetent BALB/c mice. The antitumor activity of NP73-102 was in part attributed to apoptosis of tumor cells. Western blot and immunohistochemistry staining indicated that the transcription factor, nuclear factor-kappaB, was inactivated, whereas the level of tumor suppressor retinoblastoma protein was up-regulated in the lungs of NPRA-deficient mice. Furthermore, expression of vascular endothelial growth factor was down-regulated in the lungs of NPRA-deficient mice compared with that in wild-type mice. These results suggest that NPRA is involved in tumor angiogenesis.
It was also reported that atrial natriuretic peptide receptor A (NPRA) protein is expressed in various tumor cell lines, including the androgen-independent human prostate cancer (PCa) cell line DU145, but not in NIH 3T3, a normal mouse fibroblast cell line, and NHBE, a normal human bronchial epithelial cell line. Further, NPRA protein is also detectable in the human PCa cell line PC3. However, to date the expression levels of NPRA in human tumor tissues is largely unknown and the clinical relevance of NPRA is unclear.
Prostate cancer (PCa) is the third leading cause of death among men in America [1, 2]. The mortality from PCa results from metastases to bones and lymph nodes and progression from androgen-dependent to androgen-independent disease. While androgen deprivation has been effective in treating androgen-dependent PCa, it is ineffective in treating advanced PCas, the primary cause of mortality. Epidemiological and histopathological studies have implicated inflammation in the pathogenesis of PCa [3-5]. Studies have consistently shown a decreased risk of PCa among men who regularly take aspirin or other non-steroidal anti-inflammatory drugs (NSAIDs) [6-8]. Despite beneficial effects, the side effects from using high doses of COX-2 inhibitors for cancer prevention are a major concern. These observations emphasize the need for development of new effective treatments for advanced PCa.
The family of natriuretic peptide hormones has broad physiologic effects. In addition to vasodilation, cardiovascular homeostasis, sodium excretion and inhibition of aldosterone secretion, they have been implicated in immunity and inflammation [9-18]. The effects of atrial natriuretic peptide (ANP) are mediated by its interaction with the cell surface natriuretic peptide receptor A (NPRA; high affinity) and natriuretic peptide receptor C (NPRC; low affinity). In patients with prostate tumors, the immune response plays a large part in the progression of the disease and it is likely that the NPRA system is involved; but the role of NPRA in human cancers remains unknown. The peptide NP73-102 [14], whose sequence is immediately N-terminal to the ANP peptide, is an inhibitor of NPRA (iNPRA). NP73-102 does not bind to NPRA but blocks its expression, and it has been shown that it possesses bronchodilatory, anti-inflammatory [14, 16, 19, 20] and anti-tumor activity [19].
It was previously reported that mice deficient in NPRA (NPRA-knockout, KO) exhibit significantly decreased inflammation [16, 19-21]. Furthermore, it was found that NPRA-KO mice do not permit growth of implanted human lung cancer, melanoma and ovarian cancer cells [19], suggesting that NPRA may be a novel therapeutic candidate.